Improved tuberculosis (TB) vaccines will be necessary to control the current pandemic of TB, which is out of control in much of the world. The development and pre-clinical evaluation of new TB vaccines require biologically relevant animal models in which to quantify the protective efficacy of candidate preparations. Much of the previous work in this area has been performed with two small animal models of TB, the mouse and the guinea pig. While these models have contributed much to our understanding of the determinants of vaccine-induced resistance to TB, neither may be a valid predictor of vaccine responses in humans. In addition, the co-existence of HIV and TB in many human populations may necessitate the evaluation of TB vaccines in a model of HIV infection. With regard to these latter two points, non-human primates have significant advantages over the small animal models currently employed. The long-term goal of this project is to develop a rhesus monkey model of TB and apply it to the evaluation of TB vaccine candidates. The two specific aims of the current proposal are: (1) to define the optimal dose of Mycobacterium tuberculosis delivered into the right lower lobe of the lung intratracheally which results in progressive pneumonia of at least three months duration; and (2) to define clinical endpoints (e.g., CT scans, quantitative culture of mycobacteria from BAL fluids and liver biopsies) which correlate with survival.